Project Summary The hallucinogenic drug lysergic acid diethylamide (LSD) is abused for its mind-altering effects such as vivid, surreal visual hallucinations. How LSD generates such abnormal perceptions is unknown. Because abnormal perceptions are mediated by altered activities in relevant neural circuits, investigating how LSD alters activity patterns of neural circuits in vivo is a critical step to understand the action of the drug. Here we propose a working hypothesis that LSD suppresses the ?top-down? mnemonic control of visual cortical activities from the memory areas hippocampus and medial prefrontal cortex in vivo. The suppression under LSD renders the visual cortical activities no longer influenced by recent or personal memories and therefore produces visual perceptions that no longer reflect reality or self-identify. To test the hypothesis, we will first determine whether LSD produces abnormal activity patterns in the hippocampus/medial prefrontal cortex that no longer reflect the memory of the animal?s recent behavior. Then we will examine how these abnormal mnemonic activity patterns are correlated with abnormal activities in the visual cortex and with behavioral responses to LSD. We will do so by simultaneous recording of a large number of individual neurons in rats during active tasks and during resting with and without the presence of LSD. Second, we will boost mnemonic activities in the hippocampus and medial prefrontal cortex by deep brain stimulations and determine whether the activity patterns in the visual cortex under LSD are rectified and whether behavioral responses are reduced. This project will study the neural circuit mechanism of how LSD produces its mind-altering effects and significantly advance our understanding of potential risks of recreational or medicinal use of LSD. Its outcomes will also generate insights into how hallucinations in psychiatric disorders such as schizophrenia are produced and may inspire novel treatment strategies.